Fragrant polycyclic ketones

ABSTRACT

3-Thuyopsanone and its stereo isomers(-)-3-thuyopsanone and (-)3-isothuyospsanone are prepared by oxidation of the sesquiterpene hydrocarbon thuyopsene (or its stereo isomers), or by oxidation, thermal rearrangement, saponification or acid conversion of novel intermediates derived from said hydrocarbon. The tricyclic ketones thus prepared have odoriferous properties which can be used to advantage in perfumes and perfumed products such as cosmetics, soaps, detergents, and the like.

United States Patent [191 Ohloff et al.

. [451 Oct. 1, 1974 F RAGRANT POLYCYCLIC KETONES [75] Inventors: Gunther Ohloff, Bemex, Geneva;

Hugo Strickler, La Plaine, Geneva, both of Switzerland [73] Assignee: Firmenich S.A., Geneva,

Switzerland [22] Filed: July 9, 1971 [21] Appl. No.: 161,286

Related US. Application Data [62] Division of Ser. No. 805,353, March 7, 1969.

[52] US. Cl 252/522, 252/106, 252/107 [51] Int. Cl A6lk 7/00 [58] Field of Search 252/572 [56] References Cited UNITED STATES PATENTS 8/1964 Ruzicka 260/587 X OTHER PUBLICATIONS Ito, Chem. Abs., Vol. 64, pp. 5142-5143, (1966).

Nozoe, Chem. Abs., Vol. 55, pp. 22362-22363, (1961).

Nagahama, Chem. Abs., Vol. 57, pp. 11242-11243, (1962).

Primary ExaminerJerome D. Goldberg Attorney, Agent, or FirmPennie & Edmonds [5 7] ABSTRACT 1 Claim, No Drawings 1 FRAGRANT POLYCYCLIC KETONES and to new odoriferous compositions comprising them. Formula I represents a ketone called thuyopsanone which because of its asymmetry centers comprises several odoriferous configuration isomers.

The invention also relates to methods for preparing some of said isomers and to intermediates used in said methods.

lsomeric ketones having general formula I have been found to possess very interesting odoriferous properties and are therefore useful in the perfume industry. They can be used with advantage in the preparation of perfumes and perfumed products, e.g., cosmetics, soaps, detergents and the like. Furthermore, contrary to many other odoriferous substances they are remarkably stable toward bases so that they can be used advantageously to perfume alkaline soaps and bleaching powders.

Compounds limpart to the compositions to which they have been added a very natural and harmonious woody fragrance. In certain cases the addition of compounds I to odoriferous compositions results in the development of a fragrance characterised by its freshness and cleanliness. The proportions in which the new compounds may be added to produce the desired fragrance vary between wide limits and depend on the type of perfumed product and on the effect sought. In some cases very small amounts, for example of the order of to 500 ppm by weight of the total of the product are enough to produce interesting results. In other cases, amounts of 0.001 to 10 percent by weight of perfume composition constitute a useful range. In further cases, particularly when dealing with unfinished products such as modifiers or concentrates which serve as basic ingredients for the preparation of perfume compositions, higher concentrations of the new compounds may be desirable, for instance up to percent or more. I

The concentration ranges given above should not be deemed as limiting. Thus in some special cases where rather peculiar effects are sought, concentrations falling outside the ranges mentioned hereinbefore may be necessary. Specific examples described hereinafter will illustrate the utilisation of the new fragrant compounds.

According to the invention, some of the configuration isomers comprised by formula I can be prepared by the oxidation, by means of an oxidant, of thuyopsene, a sesquiterpene hydrocarbon, either synthetic or natural having the general formula Thuyops'ene possesses two asymmetry centers and can have therefore 4 optically active isomeric configurations (2 diastereomearic pairs). Each one of these configurational isomers can be used as a starting material in the process of the invention and each one leads to the formation of different configurational isomers of thuyopsanone I. Thus, using optically active natural thuyopsene, extracted from the oil of certain conifers [see for instance I. Am. Chem. Soc. 86, 2884 (1964); Acta Chim. Scand. 17, 738 (1963)] results in the formation of the following thuyopsanone isomers:

and in the presence of an energy-transfer sensitiser.

When using this type of oxidant and thuyopsene as a starting material, a new intermediate of formula II A thuyopsen-3-ol is first formed, which subsequently isomerised with an acid to thuyopsanone.

The conditions under which the oxidation of thuyopsene can be carried out depend upon the nature of the oxidant selected. Thus, when using a peracid, the oxidation can be performed in an organic solvent such as for instance an organic acid, a chlorinated solvent, e.g., chloroform or methylene chloride, an ester such as ethyl acetate and a hydrocarbon such as xylene or toluene. The oxidation can be carried out at temperatures comprised approximately between 60 and C. but, for practical reasons, preferably comprised between 0 and 50 C. It is advantageous but not critical to first strongly cool the solution to be oxidised and add the peracid at such a rate that the heat of reaction maintains the temperature between approximately 20 and 40 C. The temperatures indicated herein'should not be considered as absolute limits. However, operating outside of these limits may cause-lower yields or reaction control difficulties. The peracid used according to the above modus procedure can also be generated in situ by adding H to the'reaction mixture, the solvent for the latter consisting partly or entirely of the acid or anhydride precursors of said peracid. Thus, the organic acid solvent or solvent component can be for instance acetic acid, acetic anhydride or formic acid.

After the oxidation of thuyopsene by a peracid is completed, the resulting thuyopsanone can be isolated via different routes. For instance:

1. The mixture can'be distilled to eliminate the volatile solvents and the acid derived from the peracid used in the oxidation, then the residue is fractionated according to usual means to isolate the thuyopsanone, or

2. the reaction mixture may be allowed to crystallise whereupon a solid of formula a wherein R is an acyl group derived from the peracid used in the oxidation, can be isolated. This solid when heated leads to a mixture of thuyopsanone and alcohol of formula ll. According to the invention, the latter is isomerised with an acid to thuyopsanone as described hereinafter in more detail; or 3. the above solid glycol monoacylate can be saponified to the corresponding glycol, the latter being also subsequently isomerised to thuyopsanone with an acid as mentioned above.

When oxidising thuyopsene with for instance chromyl chloride, the former is dissolved in a solvent such as a chlorinated solvent, e.g., carbon tetrachloride or trichlorethylene, or an inert solvent such as cyclohexane or petroleum ether, and the oxidation is carried out at a temperature comprised for instance between 0 and 50 C. but preferably between and C. for easier control. This results in the formation of a for easier control. This results in the formation of a voluminous precipitate, the nature of which has not been entirely determined (possibly a complex of the oxidation product and solvent) and which is preferably treated with aqueous sodium bisulphite in order to effect the separation of the desired ketone formed by the oxidation.

When performing the oxidation of thuyopsene by means of oxygen, a stream of this gas, either pure or in admixture with other gases such as for instance nitrogen, helium or carbon dioxide, is bubbled into a solu-' tion of thuyopsene and a catalytic amount of an energy transfer sensitiser in an organic solvent such as an'alcohol e.g., methanol, ethanol, propanol, isopropanol and butanol. or a hydrocarbon e.g. benzene, xylene and toluene, or an ester e.g. ethyl acetate, ethyl propionate, butyl acetate and the like, or mixtures of at least two of the above said solvents at temperatures comprised between 20 and 50 C., preferably at room temperature, and under continuous irradiation.

Conventional mercury or sodium vapour arcs can be used as sources of actinic radiations for irradiation purposes. As energy transfer sensitisers, most current sensitisers such as eosine, porphyrines, chlorophyll or Rose-Bengale can be used. For economic reasons, Rose-Bengale is preferred. After the take up of oxygenis completed the reaction mixture is treated with a l l ll Strong acids such as for instance hydrogen chloride,

i sulphuric acid, phosphoric acid and perchloric acid can be used to isomerise the hydroxy derivative lla into ketones la and lb. For convenience sulphuric acid is perferred.

The thuyopsanone which results from carrying out lthe oxidation process described hereinbefore with natural thuyopsene can be separated into its configurational isomers '(-)-3-thuyopsanone la and (,-)-3- isothuyopsanone lb by conventional means, for in- ;stance preparative vapour phase chromatography or lfractional distillation followed by crystallisation of the resulting fractions of distillation. la and lb can be used i together or independently in the perfume industry. Since their olfactive properties are closely related it is generally more economical to use mixtures of la and lb.

According to another process of the invention, (-)-3- thuyopsanone la and (-)-3-isothuyopsanone lb, respec- Etively, are produced by the oxidation, by means of an j oxidant, of the corresponding new alcohols llla and lllb .respectively having the formula "OH --OH I and IIIa. IIIb amaze -Lara tararaiaaaa vention can be prepared from thuyopsene according to known methods. Thus, for instance, natural thuyopsene can be hydroborated [see for example H .C. Brown, Hy-

droboration, Benjamin Inc., New York (1962)]; then the hydroboration product can be oxidised by means of alkaline H 0 This reaction which results in theformation of llla is illustrated below 1) 13,11, "0H 1 -Continued l I 2 3,0,[KOH Ingredients Parts by weight ly l I Phenylethyl alcohol 1 70 f I, s Bergamot Rt) Ina Amyl salicylatc X0 Linalyl acetate 80 Terpineol 100 A mixture of isomeric alcohols 111a and lllb can be E"f"? avandln Oll 100 obtained by catalytic hydrogenation of alcohol Ila, fol- Tom 900 lowing usual procedures. This reaction is illustrated l0 betow .22..

- When g. of the mixture of ketones la and lb aspre- Hz/PtOz pared according to Example 4 were added to 90 g. of

ma the above mixture, they imparted to the latter a very 5 natural and harmonious woodynote. EXAMPLE 3 Ha I Preparation of a cosmetic perfume composition Alcohols Illa and lllb can then be separated from A perfume Composition for cosmetic use was ning band column or preparative vapour phase chromatography.

1n the following Examples which illustrate the inven- Ingredients Parts by weight tion in a more detailed manner, the temperatures are each other by usual means, e.g., distillation on a spinpared by mixing together the following ingredients Undecanal at 10% [5 given m degrees centigrade. Decanal at 10% 20 Dodecanal at 10% 5 EXAMPLE 1 Dimethylacetyl-tert.-buty1idane 20 lndole at 10% 10 Preparation of a perfume extract gz'fgfi gfigz A perfume extract was prepared by mixing the fol- Linulyl E 5,, 3O lowin in redients Linalonl 70 g g Citronellyl acetate 20 Citronellol 100 Rose oxide at 10% 10 Ingredients Parts by weight Piperonal 50 Styrax oil 20 Jasmine absolute 5 Cinnamyl alcohol 10 Rose of May absolute 5 Phenylethyl alcohol I20 Coumurin m wtsomethylionone I r 220 Methylnonylncetaldehyde at 10% 10 v Fi i Undecanal at 10% 40 g i a Methylphenylcarhinyl acetate 40 H r? Id h d Y-Undecalactone at [(1% 20 B Truman e y e s Exaltone at 107: 20 f li lr Olihan oil 10 40 T il 0 Oak moss absolute l0 Musk ketone 21) Musk amhrette 20 *In drethyl phthalate. Oil of lahtlanum 20 Civct degreased. at 10% lsohutyl salicylate 4a The addltion of 40 g. of ketone la to 960 g. of the 9 r 5 above composition resulted in a perfume composition Hvtlroxvcltronellal 80 "IAmylicinnamuldchyde 4() for cosmetlcs possessing a very fresh and clean note. Bergamot 100 Jasmine synthetic :80 EXAMPLE 4 Rose svnthetie (l a-lsom ethylionone 100 Preparation of the mixture of ketones 1a and lb 900 50 Thuyopsene (20.4 g.) prepared by the distillation of Hiba-Wood oil, sodium acetate (10.2 g.) and methylene chloride (50 ml.) were stirred for 1 hour at room When 10 g. of the mixture of (-)-3-thuyopsanone and temlgerature' To the m1 xture down to to (-)-3-isothuyopsanone prepared according to Example T percent Peracenc F (zl Y added 9 4 were added to 90 g. of the above mixture the latter wise in the course of 15 minutes. Durmg the addition a developed a very natural and harmonious fragrant note the temperature was "lamtamed between 0 and Of woody nature After standtong overnight at room temperature, the

- mixture was filtered and poured into ice-water. The or- EXAMPLE 2 ganic layer was separated, neutralised with concentrated aqueous Na CQ dried and then distilled. The mixture of ketones 1a and lb b.p. 96-99/0. 15 Torr was obtained in 70 percent yield. It gave the following constants:

' ln diethyl Phthalatc Preparation of a soap perfume A soap perfume was prepared by mixing the following ingredients Ingredients Parts by weight Geranium Bourbon oil 3 Analysis: Calculated for C, -,H ,O C 81.76% H 10.98% (love oil 5 Found C 81.14% H 10.74% Trichlormethylphenyl acetate Musk Xylene coummin 50 Comparable results were obtained when peracetlc Benzyl acetate acid was replaced, in the present Example, by other Analysis:

peracids such as perbenzoic or .m-chloroperbenzoic acids, dissolved in methylene chloride.

EXAMPLE Preparation of the mixture of ketones la and lb To thuyopsene (20.4 g., 0.1 mole) in CC], (20 ml.) a solution of CrO Cl (31 g., 0.2 mole) in CCl, (130 ml.) was added dropwise, in the course of 45 minutes, with vigorous stirring and cooling. During the addition, which resulted in the formation of a voluminous precipitate, the temperature was maintained between 13 and 20 C. After stirring overnight at room temperature, the precipitate was separated by suction-filtration and was added to an excess of an aqueous sodium bisulphite solution. The crude ketone was extracted twice with ether and the extracts were washed with the following fractions: water (twice); 10 percent aqueous NaHCO EXAMPLE 6 Preparation of the mixture of ketones la and lb a. Hydroxyl compound 11 A solution of thuyopsene (612 g., 3 mole) and Rose- Bengale (20-50 mg.) in methanol (2 litres) was irradiated with a 200 W, sodium vapour lamp, while a stream of oxygen was introduced into the'mixture. After 18 hours. 70 litres of oxygen had been consumed and the oxidation reaction was stopped. A solution of sodium sulphite (415 g., 3.3 mole) in 2 litres of water was added with stirring to the mixture, the temperature being kept below 60 C. The organic layer was separated and the aqueous phase was extracted twice with ether. The main layer and the two extracts were mixed, washed with water and after the usual procedure, 203.3 g. of hydroxyl compound 11, b.p. 96/0.02 Torrwere isolated by distillation. Yield 30.8 percent. The product was crystallised twice from petroleum-ether, m.p. 84-85. [01],, (10 percent solution in CHCl;;) 19.0.

sex

EXAMPLE 7 Preparation of ()-3-thuyopsanone la and (-)-3- isothuyopsanone lb A mixture of thuyopsene (20.4 g.. 0.1 mole) prepared by the distillation of Hiba wood oil [Thuyopsis dolabrata]. sodium acetate (2 g.) and ethyl acetate (50 ml.) was stirred with cooling. A 42 percent peracetic acid solution (21 g.) was added dropwise, the temperature being maintained below 60 by means of refrigeration.

Then the solution was poured into ice-water and the organic phase separated. The latter was washed with water and neutralised with Na C0 After drying, the solvents were removed by distillation under reduced pressure whereupon the residue was heated in order to remove the greater portion of the combined acetic acid. After distillation of the residue there were obtained 12.6 g. (57.2 percent) of a mixture, b.p. /0.001 Torr, containing 17.5 percent of thuyopsanone, m.p. 68, and 82.5 percent of isothuyopsanone,

m.p. 40. This composition was established by gas chromatographic analysis. By repeated crystallisation of the product in petroleum ether (boiling range 3050) pure isothuyopsanone, m.p. 38'-40; [01],, --l56 (CC1 was obtained.

Analysis: calculated for C, =,H, ,.O C 81.76% H 10.98% found C 111.93% 1-1 10.87%

(boiling range 60-80) and had a m.p. of 66 68;

Analysis: calculated for C,-,H2|O C 81.76% H 111.9871 found C 81.79% H 10.88%

u.v. spectrum (ethanol): 2010 A (6 #3399 2830 A (e 28.5). NMR spectrum (Varian HA100): 0.64

(3H, s), 1.2 (3H, d, J=0.7 cps), 1.1 and 1.2 (2 X 3H, s), 0.6- 0.8 (2H, broad band), 1.3 1.9 (7H), 2.1 2.3 (2H, d, .1 1.5 cps), 2.3 2.55 (1H, broad band) ppm 8.

EXAMPLE 8 Preparation of (-)-3-thuyopsanone and of (-)-3- isothuyopsanone a. (-)-A -Thuyopsen-3-ol 102 g. of natural thuyopsene (0.5 mole) were dissolved in 2 litres of methanol. Then a spatula point of Rose Bengale, dissolved in 5 ml. of 5 percent aqueous Na CO was added to the solution. An oxygen current was passed into the mixture at 20 under irradiation. After 7 /2 hours 10.6 litres of 0 had been absorbed percent). To the mixture cooled with ice was added dropwise a solution of 131.5 g. (0.5 mole) of triphenylphosphine in 350 ml. of ether. Stirring was continued until complete disappearance of the peroxides. After concentration in vacuo Ph=1PO was removed by filtration, the filtrate was diluted with water andthen extracted 3 times with ether. The extracts were treated as usual, and after separation of 3.4 g. of (-)-A"- calculated for C,,,H O found (secondary thuyopsenol) Analysis:

[a],, =25.6 (Cl-lCl NMR spectrum: 0.60 (3H, s), 1.13 and 1.04 (2 X 3H, s), 0.18 0.75 (2H, broad band), 1.2 2.2 (9H), 4.08 (1H, broad band), 5.0 (2H, d, J 0.9 cps) ppm 8. b. (+)-3-thuyopsanol and )-3-neoisothuyopsanol 0.85 g. of (-)-A -thuyopsen-3-o1, prepared according to the procedure described in paragraph (a), were dissolved in 10 ml. of ethyl acetate. After the addition of 0.09 g. of PtO the solution was hydrogenated as usual. After 1 hour the solution was filtered, the solvent was eliminated in vacuo and 0.75 g. of substance was collected. Gas-chromatographic analysis showed the presence of a constituent A (45 percent) and of a constituent B (35 percent) beside the presence of unidentified impurities.

. Constituent A was separated by perparative vapour phase chromatography and identified to be (+)-thuyopsan-3-ol, m.p. 115. NMR spectrum: 0.53 (3H, s), 1.1 (3H, d, J =0.4 cps), 1.08 and 1.0 (2 X 3H, s), 0.1 0.8 (2H, broad band), 1.2 2.2 (11H), 3.15 1H); then constituent B was identified to be (-)-neoisothuyopsan-3-ol, m.p. 102 104. [01],, l 6.8.

c. (+)-3-Thuyopsanol Under an atmosphere of argon, at the diborane produced by the reaction of NaBl-l, (100 g.) in 1 litre of diglyme with boron trifluoride etherate (400 g.) was introduced into a solution of thuyopsene (105 g. 01,, 90) in dry tetrahydrofuran (250 ml.). The reaction mixture was allowed to stand overnight then the excess of B 11 was decomposed with a little water.

A solution of 30 percent H 0 (30 g. and 12 percent aqueous KOl-l (60 g.) was added dropwise at room temperature. After 2 days at room temperature, the mixture was extracted with petroleum ether (b.p. 30 50). The extract was treated as usual and gave, after distillation under reduced pressure, 64 g. of crude 3- thuyopsanol. An analytical sample was obtained by crystallisation from petroleum ether (b.p. 80 100) m.p. 113 --1 14; [01],, +l6 (CHCl The spectral data were similar to those described under paragraph (b), above.

d. Oxidation of (-)-3- neoisothuyopsanol (analogy with J. Am. Chem. Soc. 83, 2952,(,1961)) (+)-3-Thuyopsanol. m.p. 115 (0.3 g.) prepared according to the methods described under paragraphs (b) or (c) was dissolved in the minimum amount of ether; at this solution was added dropwise to a solution of sodium bichromate dihydrate (0.135 g.). H 50 (0.1

(+)-3-thuyopsanol and ml.) and water 2 ml.). After stirring 2 hours at 25, the mixture was extracted with ether and, after the usual treatment, the crude product was fractionated with a spinning band column to give 66 percent of (-)-3- thuyopsanone. The analytical data were the same as these described in Example 7.

When in the above Example (-)-3-thuyopsanol was replaced by (-l-)-3-neoisothuyopsanol, (-)-3- isothuyopsanone was obtained in comparable yields.

EXAMPLE 9- Preparation of (-)-3-thuyopsanone and (-)-3- isothuyopsanone a. Glycol monoacetate of formula 39.5 percent Peracetic acid (4,210 g.) was added dropwise between 18 and 35 to a stirred mixture of natural thuyopsene (3,565 g.). toluene (10 l.) and anhydrous sodium acetate (350 g.). During the addition the reaction temperature was controlled by means of a cooling bath. The reaction mixture was washed until neutral and concentrated. The residue was left overnight at 0. The solid which separated (1,880 g.) was removed by suction and the mother-liquors were treated as described in Example 7 to give a first fraction of thuyopsanone isomers. I

The solid monoacetate was crystallised in petroleum ether (b.p. 50 70), m.p. 108 109. NMR spectrum (CCl,): 0.54 (3H, s), 1.0 (3H, s), 1.1 (3H, s), 1.3(31-1, s), 2.0 (3H, s), 4'.62 (1H, d of d, J =4 and 12 cps) ppm 5 b. Decomposition of the glycol-monoacetate by heat g. of the glycolmonoacetate prepared according to the description of paragraph (a) above were subjected to two successive distillations between and 160. The titration of the distillate showed that all the combined acetic acid had been removed. The distillate was washed until neutral then it was shown, by vapour phase chromatography to be an approximately 1 1 mixture of thuyopsanone (2 isomers) and alcohol of formula lla. This mixture was used as such in the next step. The yield was nearly 100 percent.

0. lsomerisation of the lla component The mixture of thuyopsanone isomers and alcohol lla (130 g.) prepared according to paragraph (b) was dissolved in ml. of ethanol. 50 percent H SO (50 ml.) were added dropwise and the solution was kept 4 hours at 40. ln case of turbidity a few m1. of ethanol were added to clarify the solution. The mixture was diluted with water and extracted with petroleum ether (b.p. 50 70). The extract was treated as usual and gave after distillation 120 g. of practically pure thuyopsanone. The ketone comprised an approximately 1 1 mixture of (-)-3-thuyopsanone and (-)-3 isothuyopsanone which were separated by usual means (see Example 7).

EXAMPLE 10 Preparation of (-)-3-isothuyopsanone a. Saponification of the glycol-monoacetate of formula The glycol was recrystallised in petroleum ether (b.p. 30 50), m.p. 78 80. NMR spectrum (CCl 0.55

(3H, s), 1.0 (3H, s), 1.36 (3H, s), 3.0 3.5 (3H, complex band);'this spectrum indicated the probable pres ence of at least 2 configurations.

b. Treatment of the glycol with acid.

A solution of the glycol (10 g.) was prepared according to the description of paragraph (a), .10. percent H (5 ml.) and 50 ml. of petroleum ether (b.p. 80 100) was boiled and stirred for 2 hours. The solution was neutralised and treated as usual to give 9 g. of percent pure (-)-3-isothuyopsanone. The 10 percent impurity consisted of 6-)-3-thuyopsanone as shown by vapour phase chromatography.

We claim:

1. A perfume composition comprising in a perfume carrier, an effective fragrance imparting amount of at least one configurational isomer of the ketone of the formula said configurational isomer selected from the group consisting of r (-)-3-thuyopsanone and (-)-3- isothuyopsanone'.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,839,232 Dated October 1, 1974 I Gunther Ohloff and Hugo Strickler It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Abstract page '1, reads "isothuyospsanone" should read --isothuyopsanone-.

Column 2, line 3, reads "dias tereomearic" shouldEd diastereomeric--,

line 36 reads "in part of" should read -in part or-- line 49 reads "which subsequently" should read --which is subsequently-- Signed and sealed this 11th day of March 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C MASON v Commissioner of Patents Attestlng Officer and Trademarks FORM P0-1050 (10.69) I USCOMMDC 50376-1 69 i 0.5. GOVERNMENT PRINTING OFFICE I9! 0-366-334, 

1. A PERFUME COMPOSITION COMPRISING IN A PERFUME CARRIER, AN EFFECTIVE FRAGRANCE IMPARTING AMOUNT OF AT LEAST ONE CONFIGURATIONAL ISOMER OF THE KETONE OF THE FORMULA 